Process for the preparation of (1S,4R)-2-oxa-3-azabicyclo[2,2.1]hept-5-enes

Abstract

Enantiomerically enriched (1 S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of formula wherein PG1 is an amino-protective group, are prepared from cyclopentadiene via hetero-Diels-Alder cycloaddition with protected 1-C-nitroso-β-D-ribofuranosyl halides of formula wherein X is a halogen atom selected from fluorine, chlorine, bromine and iodine, PG2 is a hydroxyl-protective group and PG3 is a 1,2-diol-protective group.

The invention claimed is: 
     
       1. A process for preparing an enantiomerically enriched (1S,4R)-2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula 
       
         
           
           
               
               
           
         
         wherein PG 1  is an amino-protective group, the process comprising the steps of 
         (i) reacting a protected 1-C-nitroso-β-D-ribofuranosyl halide of formula 
       
       
         
           
           
               
               
           
         
         wherein 
         X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, 
         PG 2  is a hydroxyl-protective group, and 
         PG 3  is selected from the group consisting of methylene, ethylidene, isopropylidene, cyclopentylidene and cyclohexylidene; 
         with cyclopentadiene to obtain a (1S,4R)-3-(1-C-halo-α-D-ribofuranosyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of formula 
       
       
         
           
           
               
               
           
         
         wherein X, PG 2  and PG 3  are as defined above; 
         (ii) hydrolyzing the compound obtained in step (i) to obtain free (1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene (I; PG 1 =H) or the corresponding hydrohalide and the corresponding 5-O-protected D-ribonolactone by phase separation, wherein the enantiomeric excess of (I) or corresponding hydrohalide is at least 80%; and 
         (iii) introducing the amino-protective group PG 1 ; wherein step (i) is carried out at a temperature between about −80° C. and about 0° C. 
       
     
     
       2. The process of  claim 1  wherein the amino-protective group PG 1  is a benzyloxycarbonyl group and is introduced by reacting the (1S,4R)-2-oxa-3-azabicyclo-[2.2.1]hept-5-ene with benzyl chloroformate. 
     
     
       3. The process of  claim 1  wherein X is chlorine. 
     
     
       4. The process of  claim 1  wherein the 1,2-diol-protective group PG 3  is an isopropylidene group. 
     
     
       5. The process of  claim 1  wherein the steps (i) to (iii) are carried out without isolating the intermediate of formula III or the free (1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene (I; PG 1 =H) or its hydrohalide. 
     
     
       6. The process of  claim 1  wherein the protected 1-C-nitroso-β-D-ribofuranosyl halide of formula II is prepared by reacting the corresponding protected D-ribofuranose hydroxylamine of formula 
       
         
           
           
               
               
           
         
       
       with two equivalents of a hypohalite of formula M n+ (OX) n   − 
 wherein X is chlorine, bromine or iodine, n is 1 or 2 and M is selected from the group consisting of alkali metals and alkaline earth metals. 
 
     
     
       7. The process of  claim 6  wherein the hypohalite is sodium hypochlorite. 
     
     
       8. The process of  claim 1  wherein the protected D-ribonolactone obtained in step (ii) is recovered and reconverted into the protected 1-C-nitroso-β-D-ribofuranosyl halide (II). 
     
     
       9. The process of  claim 1  wherein the hydroxyl-protective group PG 2  is a triphenylinethyl group. 
     
     
       10. The process of  claim 1 , wherein the 1,2-diol-protective group PG 3  is a methylene group. 
     
     
       11. A (1S,4R)-3-(1-C-halo-α-D-ribofuranosyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of formula 
       
         
           
           
               
               
           
         
       
       wherein
 X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, 
 PG 2  is a hydroxyl-protective group, and 
 PG 3  is selected from the group consisting of methylene, ethylidene, isopropylidene, cyciopentylidene and cyclohexylidene. 
 
     
     
       12. The (1S,4R)-3-(1-C-halo-α-D-ribofuranosyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of  claim 11  wherein X is chlorine. 
     
     
       13. The (1S,4R)-3-(1-C-halo-α-D-ribefuranosyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of  claim 11  wherein PG 2  is a triphenylmethyl group. 
     
     
       14. The (1S,4R)-3-(1-C-halo-α-D-ribefuranosyl)-2-oxa-3-azahicyclo[2.2.1]hept-5-ene of  claim 11  wherein PG 3  is an isopropylidene group. 
     
     
       15. The process of  claim 6  wherein the hypobalite is potassium hypochlorite. 
     
     
       16. The process of  claim 1  wherein PG 3  is an ethylidene group. 
     
     
       17. The process of  claim 1  wherein X is bromine. 
     
     
       18. The process of  claim 1  wherein X is fluorine. 
     
     
       19. The process of  claim 1  wherein PG 2  is a trityl group having one or more substituents selected from the group consisting of C 1-4  alkyl groups and halogen atoms at its phenyl groups. 
     
     
       20. The process of  claim 1  wherein the step (i) is carried out at about −78° C.